Import Alert 17-04

(Note: This import alert represents the Agency's current guidance to FDA field personnel regarding the manufacturer(s) and/or products(s) at issue. It does not create or confer any rights for or on any person, and does not operate to bind FDA or the public).

BSE has been identified in more than 100,000 cattle in the United Kingdom and, to a much lesser extent, in several other countries. This neurological disease is a transmissible spongiform encephalopathy (TSE) and is similar to other TSEs such as scrapie in sheep and Creutzfeldt-Jakob Disease (CJD) in humans. The spongiform encephalopathies are uniformly fatal and no rapid diagnostic test for infection in living animals or humans is presently available. Current scientific information indicates that the causative agent is extremely resistant to activation by normal disinfection or sterilization procedures. A range of research projects into the exact nature of both the BSE agent and other TSE agents, host range, patterns of pathogenicity, and development of rapid ante mortem diagnostic tests is ongoing.

Since 1991, USDA has prohibited the importation into the U.S. of certain tissues and organs from ruminants from countries where BSE exists. (refer to 9 CFR 94.18). On January 6, 1998, USDA issued an interim rule listing other countries because of import requirements less restrictive than those that would be acceptable for importation into the U.S. and/or because of inadequate surveillance, which would

present a significant risk. USDA's regulations are intended to protect livestock in the United States from contracting TSEs and address known or strongly suspected modes of transmission. The USDA regulations permit, under certain conditions, the importation of some cosmetic ingredients (i.e., collagen, collagen products, amniotic liquids or

o bovine-derived materials intended for human consumption as either finished dietary supplement products or for use as ingredients in dietary supplements; or

o human food (except meat, i.e., skeletal muscle).

In March 1996, the Spongiform Encephalopathy Advisory Committee of the UK reported that 10 cases of CJD in the UK are likely linked to exposure BSE before the UK ban in 1989.

The FDA has recommended that manufacturers who use bovine by-products voluntarily investigate the geographic source(s) of any bovine or bovine material used in their products (generally neural or glandular tissue or tissue extracts). The Agency also suggested that each manufacturer develop a plan "to assure, with a high degree of certainty," that such materials are not from BSE-countries, as identified by USDA's APHIS, or from scrapie-infected sheep flocks, either foreign or domestic.

FDA considers further protective steps to be reasonable and, in an August 17, 1994, letter (Attachment B), recommended that manufacturers and importers of dietary supplements, cosmetic products, and raw materials for these finished product develop plans for ensuring, with a high degree of certainty, that specific bovine-derived materials from

BSE-countries are not being used.

Attachment A is an expanded list of those tissues presenting the highest known risk of infectivity, e.g., high-risk tissue, which are the subject of this import alert. Additional tissues may be added to this list as studies warrant and this import alert will be revised accordingly.

FDA will be gathering information on the development of BSE plans for all bovine - derived tissues and documenting the use of high-risk tissue from BSE-countries during domestic inspections under both the cosmetics and dietary supplements compliance programs. Due to the difficulty in verifying the presence of high-risk tissues in finished dietary supplements or cosmetic products, this import alert is limited to bulk lots of these tissues from BSE-affected or at risk countries listed above. However, if during wharf examinations or label reviews high-risk bovine tissues are noted in the ingredients statement, districts should follow the procedure in the Guidance section of this alert to notify CFSAN.

The United States Department of Agriculture issued an interim rule on January 6, 1998. The interim rule restricts the importation of ruminants, meat and meat products from ruminants, and certain ruminant products and byproducts not only from countries and other regions in which BSE is known to exist, but also from countries and other regions which, because of import requirements less restrictive than those that would be acceptable for import into the United States and/or because of inadequate surveillance, present a significant risk.

Guidance:

Districts may detain the shipment without physical examination, if the high-risk bovine tissue or ingredient, as listed in Attachment A, originated from one of the following Countries: Albania, Andorra, Austria, Belgium, Bosnia-Herzegovina, Bulgaria, Croatia, the Czech Republic, Denmark, the Federal Republic of Yugoslavia, Finland, France, Germany, Greece, Hungary, Ireland, Israel, Republic of, Italy, Japan, Leichtenstein, Luxembourg, the Former Yugoslav Republic of Macedonia, Monaco, Netherlands, Norway, Oman, Poland, Portugal, Romania, San Marino, the Slovak Republic (Slovakia), Slovenia, Spain, Sweden, Switzerland and United Kingdom. If an entry is detained and the importer or manufacturer has not provided within sixty (60) days documentation that establishes that the bovine derived tissue used in the product came from BSE-free cattle or from a non BSE affected or at risk country, districts should attempt to determine the status of the entry and, where possible, reach a final determination as to the entry. Sixty (60) days should be ample time for an importer or manufacturer to provide such documentation.

Districts may provide a copy of the Agency's August 17, 1994, letter (Attachment B) to importer's for their use in developing plans to assure that future shipments of bovine tissues are obtained from non-BSE countries.

Districts should be alert to entries of finished products from BSE affected countries which contain high-risk bovine tissues listed in the ingredients. When conducting field examinations and/or label reviews of finished products, such as dietary supplements or cosmetics that contain high-risk bovine tissues, contact CFSAN/Import Branch with product identity, high-risk bovine tissue used as ingredient, manufacturer/shipper, country of origin, and importer of record and for further guidance.

or FAX (202) 205-5025. FDA recommends that the plans be implemented as soon

after development as possible, and be available for review by the Agency

during inspections.

The Agency is continuing to examine all available information

about TSEs and will provide additional guidance as necessary. If

you need more information please contact Dr. Elliot by telephone

at (202) 205-5140.

We appreciate your attention to and cooperation in this matter.

Sincerely,

/s/

Linda A. Suydam

Interim Deputy Commissioner for

Operations

May 9, 1996

TO MANUFACTURERS AND IMPORTERS OF DIETARY SUPPLEMENTS:

TO MANUFACTURERS AND IMPORTERS OF COSMETICS:

As the media have widely reported, the British government announced on March 20, 1996, that new information had been gathered about bovine spongiform encephalopathy (BSE) in cattle that suggests a possible relationship between BSE and ten cases of a newly identified form of Creutzfeldt-Jakob disease (CJD), a similar fatal transmissible spongiform encephalopathy (TSE) in humans. To serve our mutual interest in protecting public health, the Food and Drug Administration (FDA) believes it is prudent to reiterate concerns we have previously expressed on this issue.

BSE is a transmissible neurologic disorder of cattle and is prevalent in

certain parts of the world. This neurological disease is one of a number of transmissible spongiform encephalopathies (TSE) known and is similar to other TSEs such as scrapie in sheep and CJD in humans. It is believed that the spread of BSE in cattle in some countries, particularly Great Britain, was caused by the feeding of infected cattle and sheep tissues to cattle. While transmission of the causative agent of BSE to humans has not been definitively documented to date, inter-species transfer has been demonstrated (e.g., mice can be infected by exposure to infected bovine tissues). Recent developments

in Great Britain raise serious questions regarding potential hazards of the consumption of animal tissues containing the causative agent of BSE.

Although there is still no definitive evidence that the consumption of bovine tissues that contain the transmissible agent for BSE cause CJD in humans, FDA is concerned that appropriate measures to eliminate the use of bovine tissues from BSE-countries be instituted industry-wide.

We strongly recommend that firms manufacturing or importing dietary

supplements which contain specific bovine tissues (see appendix A), including extracts or substances derived from such tissues, take whatever steps are necessary to assure themselves and the public that such ingredients do not come from cattle born, raised, or slaughtered in countries where BSE exists.

FDA believes that immediate and concrete steps should be taken by

manufacturers to reduce the potential risk of human exposure to the infectious agent which causes BSE in cattle.

The list of countries where BSE is known to exist is maintained by the U.S. Department of Agriculture (USDA) and codified in Title 9, Code of Federal Regulations, Part 94.18. The following is the current list:

USDA LIST OF COUNTRIES WHERE BSE EXISTS

(Current as of May 1996)

Great Britain (including Northern Ireland and the Falklands)

Switzerland

France

Republic of Ireland

Oman

Portugal

A range of research projects into the exact nature of both the BSE agent and other TSE agents is ongoing. Available scientific information indicates that these agents are extremely resistant to inactivation by normal disinfection or sterilization procedures. A number of dietary supplement products use bovine-derived tissues or extracts of such tissues as ingredients. These ingredients include, for example, specific tissues and organs or their extracts (e.g., liver powder, "orchic" extracts, ovaries, eye tissue, mammary

As ingredients in dietary supplements, charge: "The article is subject to refusal of admission pursuant to Section 801(a)(3) in that it appears to be for use as an ingredient in a dietary supplement and appears to be or may be otherwise unfit for food [Adulteration, Section 402(a)(3)]." "The article is subject to refusal of admission pursuant to Section 801(a)(3) in that it appears to be for use as an ingredient in a dietary supplement and may have been prepared, packed or held under insanitary conditions whereby it may have become contaminated with filth, or whereby it may have been rendered injurious to health [Adulteration, Section 402(a)(4)]." As ingredients in cosmetics, charge: "The article is subject to refusal of admission pursuant to Section 801(a)(3) in that it appears to be for use as an ingredient in a cosmetic product and appears to have or may have been prepared, packed, or held under insanitary conditions whereby it may have become contaminated with filth, or whereby it may have been rendered injurious to health [Adulteration, Section 601(c)." If final disposition of the bulk lot is undetermined, charge: "The article is subject to refusal of admission pursuant to Section 801(a)(3) in that it appears to be unfit for food [Adulteration, Section 402(a)(3)]." AND "The article is subject to refusal of admission pursuant to Section 801(a)(3) in that it appears to have been prepared, packed or held under insanitary conditions whereby it may have been rendered injurious to health [Adulteration, 402(a)(4)]".